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Allarming news concering resistance and the fact that the pipeline is dry.

I am scared that companies are dropping new HIV medicationsJun 17, 2010

Nelson, I emailed you before and you told me there were a few medications in research for people with resistance to all meds. But I just heard that two companies abandoned their research. What does that mean for someone like me who is waiting for new medications? I am so concerned.

Response from Mr. Vergel

Yes, I am also concerned about what is happening to drug development and its implications for those of use who are living with 3 or 4 medication class resistance who are waiting for more options. There is a belief that everyone treated with HAART has undetectable viral load, and only those who do not adhere to medications are the ones failing HIV therapy. I hear this a lot coming from doctors and researchers in meetings. People in salvage therapy have become the silent minority and if we do not speak up, our lives will be at risk. Salvage therapy advocacy is almost non-existent in this country, so we need to work together to remind companies that we are still here, and that new medications to treat new HIV targets are needed.

Several small companies working in HIV are running out of money since investors do not see HIV as a money making disease anymore.

An Australian company called AVEXA abandoned its apricitabine (a new nucleoside inhibitor) after spending years and millions on its development since their board does not think they can make money in HIV anymore (read the link "Avexa closes apricitabine program" here : http://www.avexa.com.au/news). Their drug could have helped some of us with Epivir/Emtriva resistance. A few activists and myself have sent the company a letter to ask them to reconsider their decision. I am still hopeful.

MYRIAD, a company in Utah, also abandoned their maturation inhibitor this month. The drug has had a lot of ups and downs. It may only work in 50% of naive patients and it may not work in patients like you and me who have multidrug resistance since we may have gag mutations that render this drug ineffective. So, I am not sure I blame them for putting their efforts somewhere else, but still think that other maturation inhibitors should still be explored.

GSK-ViiV is testing two second generation integrase inhibitors in people like you and me who have failed raltegravir. But it is too early to tell if this drug will help us. We will know by early 2011.

TAIMED, a Taiwanese company, have the only drug in a new class which can help people in salvage. The company is small and having problems finding sponsors that would fund their phase III study. Of course, like any new drug, it requires at least one other active medication in combination with it for it to work. But I am hopeful that its drug (ibalizumab, a CD4 monoclonal antibody provided every two weeks) combined with other drugs like GSK's integrase or non nucleoside could help us if found to work after the current studies are done.

PROGENICS (http://www.progenics.com/prod_pro140.cfm ), also a small company, also has a drug in a new class but in early stages of development (PRO 140, an entry inhibitor). I certainly hope they do not follow AVEXA and MYRIAD !

KORONIS ( http://www.koronispharma.com/KP1461forHIV.html ) also has a very interesting drug that makes the HIV develop mutations that may make it weaker when exposed to HIV medications, but the research on this drug has a long way to go before we think it can help people in salvage.

Hang in there and try to remain as stable as you can while you wait for options. Make sure that you and your doctor find the best "holding pattern" HIV regimen for you as you also take prophylaxis for PCP, herpes, and other potential OIs and co-factors that may affect your health.

Stay tuned. I am still hopeful, but I also need to do a lot of work n activism to ensure that small companies have the support they need from the FDA and community while they search for funding to get their drugs approved. At the same time, we must closely follow the work being done in immune based gene therapies that may provide another avenue to survival to some of us.

Please touch base with me periodically so that I can keep you abreast of new developments in the search for new drugs to help people in salvage therapy.

Please try to be serious at least for one time. Don't see any post of me as a personal need to complaint about the actual situation reguarding the development of future treatment options.

The exact mechanism of resistance development is not yet established and Mr. Vergel is citing this in his response. Resistance may develop after years of treatments and even with complete adherence. A possible risk which shouldn't alarm us but which we should at least take in consideration.

Many folks here are promoting and pushing possible cures or treatment improvements which will very likely be absolutely helpless, if they should ever pan out, to those who have developed resistance and need new treatments now. Sure, many are actually OK with current regimens but in foresight of the reality which awaits in perhaps in 10 years, without a cure, should at least turn on some thoughts about the things to come considering the actual pipeline. Or not?

« Last Edit: June 21, 2010, 05:36:31 PM by xman »

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hey, im totally not disregarding those with multiple drug resistances. but i was told by my physician that with really good adherence, the chance of developing resistance to the meds one is currently taking is very very very low. So i was under the impression that multi-drug resistance is usually the result of acquisition, or with bad adherence. Isn't that why most studies now are saying that HIV-+ people are more likely to die from cardiovascular and organ failure as a result of inflammation (aka what normal people are dying of these days) instead of drug failure? And although I agree its important to discover other drugs for those currently having multi-drug resistance problems, its important to also be supportive of research "towards possible cures or treatment improvements" because those kinds of research in many ways help create new meds along the way, and vice versa. When they first discovered raltegravir, it first became a treatment option. It was only afterwards that they discovered the crystalline structure of it, which helps to better understand the virus and move towards cure research. So in many ways, research in both arenas help each other. =)

hey, im totally not disregarding those with multiple drug resistances. but i was told by my physician that with really good adherence, the chance of developing resistance to the meds one is currently taking is very very very low. So i was under the impression that multi-drug resistance is usually the result of acquisition, or with bad adherence. Isn't that why most studies now are saying that HIV-+ people are more likely to die from cardiovascular and organ failure as a result of inflammation (aka what normal people are dying of these days) instead of drug failure?

Sure. However virus resistance may in theory develop in hidden places of the body, for example the brain, where the drugs have no or poor access. Some studies presented convincing data that the risk of resistance is not totally prevented with full adherence!

And although I agree its important to discover other drugs for those currently having multi-drug resistance problems, its important to also be supportive of research "towards possible cures or treatment improvements" because those kinds of research in many ways help create new meds along the way, and vice versa.

Absolutely. On the contrary of what the most are believing here, I'm extremely hopeful that a cure will come in a not too distant future for the simple reason that the resistance issue is understimated and a timebomb which may put a serious threat in the treatment of HIV in the coming years. Studies confirm that more resistance virus is transmitted leaving the infected person with fewer options.

We are whitnessing the first decline of new approved HIV drugs. Since the beginning of HAART there was a steady development of new antivirals until now. What will happen when the first patients will show resistance to the newer integrase inhibitors like Isentress and with no further options to chose? Don't think this scenario is so distant.

« Last Edit: June 21, 2010, 06:22:02 PM by xman »

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In the past month, two companies shelved their once-promising experimental HIV drugs, citing the challenging nature of bringing a profitable product to market. Has the overwhelming success of modern-day HIV drugs jeopardized the future of new HIV treatment options?Since Matt Sharp first learned that he was HIV positive in 1988, life has been about trying to stay one step ahead of the virus. Like many, he started each new HIV drug only to have it eventually fail, followed by a wait for the next one to be available through a clinical trial, expanded access program or U.S. Food and Drug Administration (FDA) approval. That’s just the way it was—trying to outrun HIV and to hold on until science and the pharmaceutical industry developed the next best thing. There were no other options.

The last three years, however, have been kinder to Sharp. In the space of about a year and a half, from June 2006 through January 2008, four new antiretroviral (ARV) treatments were approved, all of them with the potential to work against even the most drug-resistant HIV. After Sharp started a regimen with one of these new treatments, his virus became undetectable for the first time ever. His CD4 cells, which had been depressed for years, started to inch back up, and he continues to do well today.

Sharp is not alone in his Lazarus effect. Thousands of people with multidrug resistant virus, many of whom were once quite sick, have been able to push their viral loads to undetectable levels and restore their health with the newest antiretrovirals, often in combination with each other. But what happens if their HIV accumulates additional mutations and breaks through? Unfortunately, the number of promising agents waiting in the wings for people with drug resistant virus is dwindling.

Two companies, Avexa and Myriad Genetics, suspended development of their experimental ARV treatments over the past month. From press statements, it appears that both companies determined that their drugs—apricitabine (a nucleoside reverse transcriptase inhibitor) and bevirimat (a maturation inhibitor)—could not be brought profitably to market. While neither drug was perfect, or had a certain shot at FDA approval, some activists and researchers see their failure as evidence of a paradox—that today’s highly effective drugs are hurting the development of tomorrow’s promising agents.

“The very incentives that got industry involved to develop HIV drugs are now working against us,” says Jay Lalezari, MD, the director of clinical research at Quest Clinical Research in San Francisco, who specializes in the study of drugs for people with multiple drug resistance. “But, you know, money is a driver, and you don’t expect these companies to do it for nothing,” he laments.

“It’s getting harder and harder to hit a homerun with a new HIV drug,” says Bob Huff, a longtime HIV treatment activist from San Diego. “The current drugs are very good, and most doctors and patients are fairly satisfied…. The incentive for companies to invest in developing new HIV drugs is not strong right now.”

“It’s disconcerting,” Sharp agrees. “In terms of practical issues around drug development, we do need to put our heads together and strategize about fixing the things that are broken.”

Sharp is working with Huff and Nelson Vergel, an activist from Houston, to help identify novel ways for people who’ve run out of treatment options to get their hands on multiple experimental agents at one time. The three are also looking at creative ways for companies to get drugs approved that might only benefit treatment-experienced people, a market that is increasingly small and potentially less profitable than ever before.

Sharp, Huff and Vergel express concern about options for people who have already become resistant to current meds. With apricitabine and bevirimat now out of the picture, it only leaves a couple of drugs in an advanced state of development for people with multi-drug-resistant virus. Given the uncertain nature of drug development, however, those drugs could also tank or be delayed, and it could be quite a while before something new is approved.

Sharp is not hopeless, however, and cautions that, “There’s no reason to panic. I definitely don’t think this is the end of the world.”

Lalezari agrees that things are not so bleak, at least not yet. He points out that a number of his patients are still doing well clinically, despite going for many years with very low CD4 counts and detectable virus. He stresses that it is possible to pick a regimen and stick with it for a long time, even if your viral load remains detectable. He encourages people to sit tight on such a regimen and to “try to keep this détente with the virus, and we’ll see if gene therapies or other immune therapies can be brought to bear in the future.”

Vergel is another veteran of the treatment wars and knows what it’s like to face uncertainty. He says that if his current drug regimen fails, he’s not sure what he’ll turn to. He’s not despairing, however, because he feels that he and other activists are making progress with the FDA in figuring out how to make new treatment options available, even when the traditional avenues of approval are a challenge.

In the meantime, he distills his own positive outlook for the many hundreds of people with HIV he interacts with each year through his Internet and public speaking activities. As he sums it up: “You have to give them hope.”A Good News, Bad News Story

“The bigger picture with HIV therapeutics is a good news, bad news story,” says Paul Sax, MD, clinical director of the HIV program at Brigham and Women’s Hospital in Boston. “The good news is that HIV treatment success is so high now. The bad news,” he adds, is that “the motivation to develop new drugs, especially drugs to treat resistant virus, has ironically never been lower. There’s this small group of people who have no options even with those newer drugs, and for them, the situation is very discouraging.”

Treatment success has made developing a new drug targeted toward drug-resistant virus problematic in several ways. First, we can no longer simply pit a new drug against a placebo, with no other active drugs to back it up. A number of studies have found that when people take only one active drug at a time, they quickly develop resistance to that drug. For this reason, federal treatment guidelines recommend waiting to start a new treatment, if possible, until two or three active drugs can be combined into a new regimen.

While combining two or three active agents is good for study participants, it's a headache for trial designers. This is because the difference between an experimental drug and a placebo are much smaller and more difficult to measure if their impact is masked by the potency of other powerful drugs.

Sax points to the failure of the drug vicriviroc to demonstrate efficacy over a placebo in treatment experienced participants as a perfect example of this dynamic at work. “The vicriviroc study had the old study design,” Sax explains, “which was [a background regimen chosen by drug resistance tests] plus or minus the [vicriviroc], and they didn’t see any benefit, unless you [only looked at people taking] one other active drug.”

To detect such slight differences you have to either recruit only people with one or fewer active treatments available or design trials with twice as many people. The first option goes against the grain of treatment guidelines, and Sax thinks that the challenging and slow recruitment for a number of recent studies targeting treatment-experienced patients makes it quite unattractive to the companies. Even more unattractive, however, is the second option which almost doubles the cost of the trial.

Vergel has been working with Lalezari and Steve Deeks, MD, professor of medicine at the University of California at San Francisco, to estimate the number of people in the United States with resistance to all of the existing drugs—the kind of people that Sax says would be a challenge to recruit.

Vergel estimates that there are at least 1,500 such individuals, but that number is not growing rapidly. While this may be good news from a public health perspective, it is bad news for people with highly drug-resistant HIV who are depending on the pharmaceutical industry to develop new treatment options. Corporate board members and shareholders demand the highest profit possible with the least expense. With clinical trials potentially getting more expensive and harder to recruit, and the market size staying small, it’s getting very difficult to meet those demands.

“We’re up against the fact that drug development is about making a profit,” Sharp says, “and unfortunately that’s what we have to deal with.”What the Future Holds

Sharp, who works frequently with Vergel on treatment advocacy projects, says that there are promising treatments further back in the pipeline, and that still other more innovative types of treatment are finally reaching the point where they can move in to clinical trials designed to prove efficacy and safety. What’s more, Sharp remains devoted to advocacy related to eradication: the elimination of HIV from the body.

Lynda Dee, a veteran treatment activist and the president of AIDS Action Baltimore, confirms Sharp’s experience: “Activists have met with companies over the last year, and some have said that they have internal programs looking at new drugs and eradication,” she says. “I’m hopeful that this discontinuation of the development of [apricitabine and bevirimat] doesn’t mean that all of the industry has turned tail and left the HIV field.”

Lalezari thinks that an entry inhibitor from TaiMed Biologics, an integrase inhibitor from ViiV Healthcare, and an attachment inhibitor from Bristol-Myers Squibb might have a shot further down the road. He’s less sanguine than Sharp or Dee about the prospects for antiretroviral drug development in general, given the challenges involved. “I think we could enter a period where there’s an abrupt end to HIV drug development,” he asserts. “That’s not to say that there aren’t new modalities of interest…but in terms of new direct-acting antivirals, it’s going to be very difficult,” he predicts.Protecting Your Options

Are we on the verge of returning to the days when the best that a long-term survivor could do was guard against opportunistic infections and pray to survive long enough to benefit from the next drugs to come out of the pipeline?

Perhaps not, according to Lalezari. “The thing about the treatment-experienced population, which is astonishing, is that I have a whole bunch of people that I have been following for a number of years now, who are doing just fine. They have detectable virus, and their [CD4] cells are less than 20, but their health is just great, which is not explained in my understanding of the universe.”

Sax stresses that going off treatment would be a lot worse than staying on a failing regimen. “You know, all attempts of treatment interruptions of people with drug resistant virus met with bad outcomes,” he says, “So one thing for sure, is that people should stay on something. The question of what is more difficult. It’s never been well studied.”

In the end, what’s at stake is whether new drug development can stay ahead of HIV-positive people’s needs for new treatment options. Vergel points out that those who’ve yet to develop drug resistance can preserve their future options by finding a tolerable effective treatment and adhering to it religiously. In this regard, the possibility of a dry spell in new drug approvals could encourage people not to take for granted that new options will inevitably keep coming down the pike. “Fear,” Vergel says, “can be a good motivator” by way of emphasizing the importance of treatment adherence.

For people who’ve run out of new options, there is still reason for hope. It is possible to stay clinically healthy despite a failing ARV regimen, as Sax and Lalezari point out, and there are ways to minimize the risk of developing resistance to the experimental agents that might come later. Vergel tries to remind people of that and tells them “to not come from a place of despair.”

Sax thinks it will be helpful for researchers and health care providers to pool together their knowledge and resources to figure out the best care models for people who’ve run out of treatment options, arguing that since few providers have large numbers of such individuals it is difficult to become an “expert” in treating them. He thinks that activists and groups such as the Forum for Collaborative HIV Research in Washington, DC, can aid in that process.

Despite the challenges involved in developing the next generation of HIV therapies, Sax believes in remaining optimistic, especially with his patients who’ve run out of options. He tells them: “Press on. Drug development has helped us in the past. We hope it does again in the future.”

I know docs like Gallant and Young as well as others say with good adherence there is no reason a person's regimen couldn't last indefinitely. They both have said they have many patients on the same regimen for 10 years now.

Some of you will remember my post about my partner, brother, and even medical personnel suggesting I consider sueing the hospital for putting me on mono therapy of Sustiva. This no doubt caused my K103N mutation and resistance to Sustiva (Atripla) and Nevirapine. I didn't know how many regimens were avaliable to an HIVer. I wondered what if I couldn't tolerate a certain regimen for some reason. I just didn't know how serious losing a regimen was. Since it caused cross-resistance to Nevirapine, doesn't that mean I've actually lost more than Sustiva/Atripla. The docs tell me losing the NNRTI's shouldn't be a big deal. Still, I always wonder what if in the future I needed those options. I guess I'll cross that bridge when/if I get there.

So after losing regimens already before even starting meds, I do worry about resistance issues and a slow-down in new drugs. I realize the main point of the thread focused on those who are/have run out of most options and are resistant to just about everything. That is a scary situation. I've read many of Mr. Nelson's posts about his situation.

I know docs like Gallant and Young as well as others say with good adherence there is no reason a person's regimen couldn't last indefinitely.

This is based on Robert Siciliano's findings that residual viremia in an undetectable viral load is not actively replicating or evolving. The only way for mutations to arise would be if the small amount of virus present when one is undetectable were actively replicating and based on Siciliano's findings, it isn't.

I know docs like Gallant and Young as well as others say with good adherence there is no reason a person's regimen couldn't last indefinitely

I had quite a boring and lonely weekend this past weekend because I know I was infected last 4th of July. So, I laid around feeling sorry for myself, reading the forums, and doing my ritual Google searches for a miracle cure. One of the things that I came across was the online videos and slides from CROI 2010 and I ended up spending about 10 hours watching/listening to all of the professionals talking about the current and future state of HIV/AIDS research. It was fascinating information and I was surprised that I could follow and understand most of it. What I came away with that made me realize that it's time for me to start moving on is that being undetectable is where I want to be and that if I maintain my 100% adherence, this virus isn't going to be able to hurt me. It might hurt my chances for meeting "Mr Right", but it's not going to control MY life. We will just have to learn to live in the same body until someone figures out to serve it with eviction papers.

Of course, there are toxicity issues with these meds that will have to be dealt with, but I suspect those issues are going to be dealt with in the near future whether or not the miracle workers can figure out how to completely eradicate HIV.

The major issue these days seems to be the so called "reservoirs" where dorment/latent HIV persists and is occassionally released. The meds can't get to the latent virus until it's released into the blood stream because the meds don't "know" where to go. The fact that the virus is virtually killed and is not reproducing means that there are not significant dangers of mutations occuring that would be resistant to the meds that are keeping it under control. IF that is, in fact, the case, then I don't see how 100% adherance to a protocol that is effective can't last forever.

Just my 2 cents...

Blessings to all of you out here for the information and support that you provide!

if you're interested in the CROI slides, the link is below. For all I know, that link may have already been published out here somewhere in another thread. There is a great presentation about whether or not a cure for HIV is possible and I think the take away from the speaker is a resounding "yes, it can be".

For people like you who have had virological proof of treatment potency and adherence, there's little reason to think that you're at significant risk of having the treatment poop out. Indeed, most cases of failure or drug resistance emerge in the first months of treatment. I've got many patients who have been successfully suppressed, going on 10 years (or more). So, as long as you continue to have access to, and adhere to your medications, I think that your future should be a healthy one.

Drug resistance is possible without being adherent and all. I know because it has happened to me. I have very few choices in meds now. I always took my meds same time every day and every day for that matter. I still got resistant to many drugs on the market. Strangely enogh i still can take one of the worst ones AZT. I am trying Combivir Reyataz Norvir boost and Isentress at the present time i hope they stay working for me for a long time because I am resistant to many HIV drugs at present and not my fault either.

Thak you for taking the time to read this.

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1997 is when I found out, being deathly ill. I had to go to the hospital due to extreme headache and fever. I fell coma like, two months later weighing 95 pounds and in extreme pain and awoke to knowledge of Pancreatis, Cryptococcal Meningitis, Thrush,Severe Diarea, Wasting, PCP pneumonia. No eating, only through tpn. Very sick, I was lucky I had good insurance with the company I worked for. I was in the hospital for three months that time. (2010 Now doing OK cd4=210 VL= < 75)I have become resistant to many nukes and non nukes, Now on Reyataz, , Combivir. Working well for me not too many side effects. I have the wasting syndrome, Fatigue . Hard to deal with but believe it or not I have been through worse. Three Pulmonary Embolism's in my life. 2012 520 t's <20 V load

Drug resistance is possible without being adherent and all. I know because it has happened to me. I have very few choices in meds now. I always took my meds same time every day and every day for that matter. I still got resistant to many drugs on the market. Strangely enogh i still can take one of the worst ones AZT. I am trying Combivir Reyataz Norvir boost and Isentress at the present time i hope they stay working for me for a long time because I am resistant to many HIV drugs at present and not my fault either.

Thak you for taking the time to read this.

It's not only about adherence of course. The other aspect is that it has to be enough drugs to suppress the virus and this usually means three different drugs from at least two different classes.